In the western world, many deaths occur suddenly and unexpectedly, particularly as a consequence of trauma. Medically, “trauma” refers to a serious or critical bodily injury, wound, or shock which in some cases may require resuscitation therapy. Trauma is often associated with trauma medicine practiced in hospital (such as in hospital emergency rooms), in emergency transport environments (such as in ambulances), or at out-of-hospital environments where a trauma has occurred, such as domestic or industrial accidents, transport accidents, the battlefield, and terrorist attacks.
Trauma is a leading cause of death among children and all individuals to age 34 years and a major cause of death in the older population resulting in loss of productive life-years with substantial societal costs. This includes deaths resulting from burns, heart attacks, strokes and other cardiovascular events. Deaths can also result from shock or other complications that may occur as a consequence of trauma.
Less than 3% of these unconscious trauma patients will advance to acceptable outcomes. Many survivors require institutional care after 3 months and a significant proportion remain permanently disabled. About 20% of soldiers injured in the battlefield will die, and 90% of deaths occur before reaching a hospital because of shock during emergency transport. More recent statistics suggest that 50% of deaths in potentially treatable combat injuries are due to acute blood loss, making it the leading cause of death on the battlefield.
Shock is a circulatory dysfunction causing decreased tissue oxygenation and accumulation of oxygen debt, which can ultimately lead to multi-organ system failure if left untreated. The most common form of shock in both paediatric and adult trauma patients is hemorrhagic or hypovolemic shock (not enough blood volume). Cardiogenic shock (not enough output of blood by the heart, see below) is also a common form of shock. Shock as a result of blood loss is a frequent complication of trauma. About half of trauma deaths occur during the first hour after injury from a profound compromise in cardiopulmonary and cerebral function. The signs and symptoms of shock include low blood pressure (hypotension), overbreathing (hyperventilation), a weak rapid pulse, cold clammy greyish-bluish (cyanotic) skin, decreased urine flow (oliguria), and mental changes (a sense of great anxiety and foreboding, confusion and, sometimes, combativeness). When blood is lost, the greatest immediate need is replacing the lost volume with blood or blood volume expanders. Provided blood volume is maintained by volume expanders, a trauma patient can safely tolerate very low blood haemoglobin levels, less than one third of a healthy person.
During trauma, the electrical properties of vital organs and tissues cannot be maintained. Falls in resting cell voltage occur during trauma and can lead to the triggering of highly injurious arrhythmias in the heart and activation of systemic inflammatory, coagulative and free radical generating processes that can lead to multiple organ failure and death. During severe haemorrhage, patients become unconscious when the mean arterial perfusion pressure decreases to about 40 mm Hg and the pulse is no longer palpable in the large arteries. When breathing stops and pulsations are no longer palpable, cardiac arrest is assumed. The mortality rate for trauma patients who become pulseless from massive blood loss and undergo emergency department thoracotomy is around 97%.
One form of shock is called “cardiogenic shock”. This may be caused by the failure of the heart to pump effectively due to, for example, damage to the heart muscle (as may result from a large myocardial infarction (heart-attack), disorders of the heart muscle (including rupture), disturbances to the electrical excitation-relaxation (or conduction) system and tamponade. Cardiogenic shock may also be caused by arrhythmias (eg ventricular tachycardia and ventricular fibrillation), cardiomyopathy, cardiac valve problems, ventricular outflow obstruction and the like. Cardiogenic shock is a medical emergency requiring immediate treatment to save the patient's life.
One cause of cardiogenic shock is a so-called “heart-attack”. This term is used to refer to a number of different conditions which lead to heart ischaemia, which leads to the death of heart muscle (typically caused by blockage of a coronary artery). The muscle death causes chest pain and electrical instability of the heart muscle tissue. This electrical instability may manifest as “ventricular tachycardia” and “ventricular fibrillation”. Ventricular tachycardia is a tachydysrhythmia originating from a ventricular ectopic focus and characterized by a rate typically greater than 120 beats per minute and must be treated quickly to avoid morbidity or mortality as it may deteriorate rapidly into ventricular fibrillation. Ventricular fibrillation is a condition in which there is chaotic electrical disturbances of the ventricles, such that they no longer beat regularly, nor pump blood effectively, but simply quiver. During ventricular fibrillation the heart muscle is affected by a poor supply of oxygen or by specific heart disorders and the ventricles contract independently of the atria, and some areas of the ventricles contract while others are relaxing, in a disorganized manner. Ventricular fibrillation leads to widespread ischaemia. Unless treated immediately, ventricular fibrillation causes death and is responsible for 75% to 85% of sudden deaths in persons with heart problems. In the USA alone there are nearly 450,000 sudden deaths per year, and in the united kingdom around 70,000-90,000 sudden deaths per year. Ventricular tachycardia and ventricular fibrillation are therefore medical emergencies because if they persist more than a few seconds, the blood circulation will cease, there will be no pulse, no blood pressure and no respiration and death will occur. Typically, medications and procedures at this time are directed towards stabilising the rhythm of the heart and, in the case of the unconscious subject with no measurable pulse, resuscitating the subject by restarting the heart, opening the airways and restoring spontaneous breathing. Amiodarone can be used to treat life-threatening heart arrhythmias, however, the drug can have serious side effects including causing cardiac rhythm irregularities and cardiac arrest itself. Other side effects of amiodarone include lung infiltration, neuropathy, tremors, thyroid disorders, nausea, low blood pressure and liver damage. Effective medications for stabilizing the heart or restarting the heart and restoring the spontaneous circulation in these emergency situations are therefore very limited or non-existent. Noradrenalin or adrenalin (with or without vasopressin) can be used in conjunction with cardiopulmonary resuscitation, however, epinephrine can exacerbate heart contractions and promote heart dysfunction by increasing myocardial oxygen consumption during ventricular fibrillation, as well as eliciting microvascular disorders. If the treatments are successful in stabilising the heart after ventricular tachycardia or ventricular fibrillation, a number of medications are then administered such as oxygen (if available to help breathing), beta-blockers (to help relax the heart), vasodilators (to help deliver more blood to the heart), blood agents (anti-coagulants, anti-platelet agents, thrombolytics and the like) and pain relievers. Apart from a few drugs to treat the heart as well as other tissues and organs, the medications are not directed to treating the cardiac tissue specifically. There is no effective pharmaceutical treatment for the failing heart muscle itself, nor for common ventricular fibrillation. If treated, this is usually treated by electrical shock (cardioversion).
Damage may also be caused to a heart upon reperfusion. One example of reperfusion damage is when a heart becomes “stunned”. In this condition, the bloodflow has been restored but the heart is functioning abnormally and may result in a further heart-attack (such as ventricular fibrillation) if not treated. Cardiac reanimation inevitably involves reperfusion of the heart with the consequent dangers associated with reperfusion injury, particularly to heart muscle. Where the muscle cells die, this is regarded as an infarction. If blood flow is restored to the cells within a short period of about 15 to 20 minutes the cells may respond to the reperfusion and survive (thus not forming an infarction) but may be “stunned” in the sense that they do not operate normally nor perform their usual function during reperfusion.
In patients who survive resuscitation where the initial event may be less traumatic, they remain at a significant risk from systemic and local inflammatory and immune activation followed by multiple organ dysfunction and failure. Multiple organ failure is believed to be the result of an excessive self-destructive systemic inflammation and immunologic functions, in which hypoxemia, tissue hypoxia/nonviable tissue, micro-organisms/toxins and antigen/antibody complexes may be involved. In particular, the activation of a number of humoral (e.g. complement, coagulation) and cellular systems (endothelium activation, neutrophils, platelets, macrophages) are believed to be involved. Neutrophils play a key role in injury to the lung, heart, kidney, liver, and gastrointestinal tract, often seen after major trauma. As a consequence there is synthesis, expression and release of numerous mediators (toxic oxygen species, proteolytic enzymes, adherence molecules, cytokines), which may produce a generalized inflammation and tissue damage in the body.
The critical core body temperature also can aggravate many of these post-traumatic secondary complications. Below 34° C. mortality increases significantly. Despite this, a number of investigators have suggested a beneficial effect of deliberate hypothermia because this may prolong the “golden hour” of trauma victims by preventing hypoxic organ dysfunction and initiation of the inflammatory response. Organ failure is also the leading cause of death in the postoperative phase after major surgery. An excessive inflammatory response followed by a dramatic depression of cell-mediated immunity after major surgery appears to be responsible for the increased susceptibility to subsequent sepsis.
Resuscitation therapy is generally regarded as any procedure which improves the management of sudden states of life-threatening illnesses or traumatic injuries, such as those from cardiac arrest, respiratory failure, hemorrhagic blood loss, neurological injury, and traumatic injuries to the soft tissues and body skeleton. Generally, resuscitation therapy deals with treating whole body oxygen deprivation. As such, current resuscitation strategies aim to optimize tissue supply and demand ratio and avoid complications of overaggressive volume replacement, which exacerbate haemorrhage, pulmonary oedema, and intracranial hypertension following brain injury.
Resuscitation therapy is very different from treating a localized “big heart attack” or a localized “big stroke”. It involves a complex interplay between multiple organ-tissue responses via poorly understood actions, which separates this science from treatments to preserve particular organs or tissues. Resuscitation is known to involve a complex biological system, with many interactions. These cannot be predicted from study of individual components. Injured organs have secondary effects on other organs, which affects the whole body and can lead to debilitating injuries and death.
Current therapies involve fluid or volume replacement that can either be crystalloid or colloidal. Crystalloids are commonly used for resuscitation therapy because they appear to be safe and help with the negative side effects of coagulation. Crystalloids have been shown to increase coagulation, an effect which seems to be independent of the type of crystalloid used. A crystalloid-induced hypercoagulable state appears to be due to an imbalance between naturally occurring anticoagulants and activated procoagulants. Crystalloids used for volume replacement can be three main types: 1) hypotonic (eg. dextrose in water), 2) isotonic (normal saline or Ringers solution with lactate or acetate) or 3) hypertonic (eg 7.5% saline). Since crystalloids are freely permeable to the vascular membrane, only about 25% remain in the blood compartment and the remainder in the body's interstitial and/or intercellular compartment leading to tissue oedema. Crystalloid resuscitation is therefore less likely to achieve adequate restoration of microcirculatory blood flow compared to a colloidal-based volume replacement strategy.
Colloid replacement therapies employ colloids, such as dextran-70, dextran-40, hydroxyethyl starch, pentastarch, lactobionate, sucrose, mannitol and a modified fluid gelatine as artificial colloids, for this purpose. There is much controversy as to the most appropriate solution for volume replacement.
Currently there is no optimal fluid composition or fluid resuscitation regimen to treat severe hemorrhagic shock in soldiers on the battlefield or civilians at a natural disaster site or injured from a terrorist attack. Indeed, the majority of approved resuscitation fluids have no intrinsic tissue protection and can trigger life-threatening inflammatory and hypercoagulable imbalances that negatively impact on the resuscitative outcome. A further challenge in designing new drug products and resuscitation therapies, in particular for the military, is hampered by logistical considerations imposed by the combat conditions themselves such as weight and practicability to transport, ease of deployment, administration in low-light environments and stability of drugs in the field, notwithstanding ensuring their safety and clinical effectiveness to increase the survival times of wounded soldiers after prolonged evacuation.
In warfare, bullets and penetrating fragments from exploding munitions frequently cause life-threatening hemorrhage. Acute hemorrhage is the leading cause of mortality in battlefield injuries and responsible for 50% of deaths in potentially treatable combat casualties. One major unmet medical need on the battlefield is how to prevent cardiac destabilization and arrest during severe hemorrhage before control of bleeding is possible. Stabilizing heart and circulatory deficiencies before shock is of paramount importance. Successful treatment of cardiac arrest requires an electrically stable and mechanically viable heart to be re-established. Currently there is no clinically effective method of stabilizing and protecting the heart from fibrillating and arresting before hemorrhagic shock. Indeed, many pharmacological interventions employed to convert the heart to sinus rhythm may unfortunately inflict additional injury and compromise cardiac resuscitability
In those severe traumatic hemorrhagic cases where the heart does not destabilize and arrest, the loss of blood volume, blood pressure and organ perfusion can lead to severe organ ischemia and eventually multiple organ dysfunction and failure (MOF) and death. MOF is the leading cause of mortality secondary to shock (hemorrhage/trauma) and resuscitation, and involves the lungs, kidneys, intestinal tract, pancreas, liver, brain and heart. Importantly, MOF is not an end-point per se but a process involving an overwhelming self-destructive, local and systemic, inflammatory responses and immunologic functions. Despite decades of research, resuscitation fluids restore tissue perfusion, however they have no specific anti-inflammatory, immunosuppression or pro-survival properties. Importantly, the activation of shock-induced inflammatory response occurs during the shock itself, during early crystalloid or colloid-based resuscitation therapy, and during final resuscitation efforts with blood replacement.
It is not known whether protection from injury from trauma could be elicited by a form of artificial hibernation. Natural hibernators possess the ability to lower their metabolic energy demand for days to months. Hibernation, like sleep, is a form of dormancy and helps to keep the animal's metabolic supply and demand ratio in balance. Remarkably, no damage occurs during these prolonged “ischemic” states, nor does the cardiac rhythm deteriorate into ventricular fibrillation. However, there is no known method of stimulating a similar response in humans, particularly trauma patients, despite the potential for substantial saving of life or minimising injury.
WO00/56145, WO04/056180 and WO04/056181 describe compositions useful to limit damage to a cell, tissue or organ by administering them in a clinical setting prior to a medical procedure. These compositions are also usually administered following diagnosis of the patient and directly to the cell, tissue or organ. However, much damage or injury to cells, tissues or organs may arise before the patient gets to the hospital and/or at hospital, for example, before substantive medical attention is available or a condition can be diagnosed.